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Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc ^Min/+ mouse model of intestinal tumorigenesis.

ABSTRACT: Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macrophages drives adenoma growth and progression in vivo in the Apc ^Min/+ mouse model of intestinal tumorigenesis. Using a transgenic C57Bl/6 mouse model of Cox-2 over-expression driven by the chicken lysozyme locus (cLys-Cox-2), which directs integration site-independent, copy number-dependent transgene expression restricted to macrophages, we demonstrated that stromal macrophage Cox-2 in colorectal (but not small intestinal) adenomas from cLys-Cox-2 x Apc ^Min/+ mice was associated with significantly increased tumour size (P?=?0.025) and multiplicity (P?=?0.025), compared with control Apc ^Min/+ mice. Transgenic macrophage Cox-2 expression was associated with increased dysplasia, epithelial cell Cox-2 expression and submucosal tumour invasion, as well as increased nuclear ?-catenin translocation in dysplastic epithelial cells. In vitro studies confirmed that paracrine macrophage Cox-2 signalling drives catenin-related transcription in intestinal epithelial cells. Paracrine macrophage Cox-2 activity drives growth and progression of Apc ^Min/+ mouse colonic adenomas, linked to increased epithelial cell ?-catenin dysregulation. Stromal cell (macrophage) gene regulation and signalling represent valid targets for chemoprevention of colorectal cancer.

SUBMITTER: Hull MA

PROVIDER: S-EPMC5519705 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc <sup>Min/+</sup> mouse model of intestinal tumorigenesis.

Hull Mark A MA Cuthbert Richard J RJ Ko C W Stanley CWS Scott Daniel J DJ Cartwright Elizabeth J EJ Hawcroft Gillian G Perry Sarah L SL Ingram Nicola N Carr Ian M IM Markham Alexander F AF Bonifer Constanze C Coletta P Louise PL

Scientific reports 20170720 1

Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macrophages drives adenoma growth and progression in vivo in the Apc <sup>Min/+</sup> mouse model of intestinal tumorigenesis. Using a transgenic C57Bl/6 ...[more]

PMID: 28729694

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Project description:With its significant contribution to cancer mortality globally, advanced colorectal cancer (CRC) requires new treatment strategies. However, despite recent good results for mismatch repair (MMR)-deficient CRC and other malignancies, such as melanoma, the vast majority of MMR-proficient CRCs are resistant to checkpoint inhibitor (CKI) therapy. MMR-proficient CRCs commonly develop from precursor adenomas with enhanced Wnt-signalling due to adenomatous polyposis coli (APC) mutations. In melanomas with enhanced Wnt signalling due to stabilized β-catenin, immune anergy and resistance to CKI therapy has been observed, which is dependent on micro-environmental myelomonocytic (MM) cell depletion in melanoma models. However, MM populations of colorectal adenomas or CRC have not been studied. To characterize resident intestinal MM cell populations during the early stages of tumorigenesis, the present study utilized the ApcMin/+ mouse as a model of MMR-proficient CRC, using enhanced green fluorescent protein (EGFP) expression in the mouse lysozyme (M-lys) lys-EGFP/+ mouse as a pan-myelomonocytic cell marker and a panel of murine macrophage surface markers. Total intestinal lamina propria mononuclear cell (LPMNC) numbers significantly decreased with age (2.32±1.39×107 [n=4] at 33 days of age vs. 1.06±0.24×107 [n=8] at 109 days of age) during intestinal adenoma development in ApcMin/+ mice (P=0.05; unpaired Student's t-test), but not in wild-type littermates (P=0.35). Decreased total LPMNC numbers were associated with atrophy of intestinal lymphoid follicles and the absence of MM/lymphoid cell aggregates in ApcMin/+ mouse intestine, but not spleen, compared with wild-type mice. Furthermore, during the early stage of intestinal adenoma development, there was a two-fold reduction of M-lys expressing cells (P=0.05) and four-fold reduction of ER-HR3 (macrophage sub-set) expressing cells (P=0.05; two tailed Mann-Whitney U test) in mice with reduced total intestinal LPMNCs (n=3). Further studies are necessary to determine the relevance of these findings to immune-surveillance of colorectal adenomas or MMR-proficient CRC CKI therapy resistance.

Dataset Information

Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc ^Min/+ mouse model of intestinal tumorigenesis.

Publications

Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc <sup>Min/+</sup> mouse model of intestinal tumorigenesis.

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Dataset Information

Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc Min/+ mouse model of intestinal tumorigenesis.

Publications

Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc <sup>Min/+</sup> mouse model of intestinal tumorigenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc ^Min/+ mouse model of intestinal tumorigenesis.